Welcome to this next Fireside Chat. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and with us today we have Ron Cooper, CEO of enGene Therapeutics. Ron, welcome. Thanks for joining us. Well, thanks for the invitation. Great to be here. So Ron, you're in the non-muscle invasive bladder cancer space. Can you just remind us, for those that are new to this story, what the value proposition is for your lead product candidate, detalimogene, and how it fits into the space? Yeah, so I think the profile of detalimogene actually fits really nicely with the needs of, of urologists. When you think about urologists at two different ends of the scale, you've got your academic urologists and your community urologists. The community is where most of the patients are, right? And so what are the community urologists looking for? We've done pretty extensive market research, and these practices, remember, are increasingly private equity held, right? So they're under increasing pressure for throughput and the like. And so when they look at product attributes, they really value almost equally efficacy, tolerability, and non-clinical benefits, ease of use, and how it fits in their practice flow and the economics of their practice flow. When you think about detalimogene, it really addresses all of those things. So with an efficacy profile that looks similar to the other agents, a very competitive efficacy profile, with a tolerability profile that's probably best in class, very low treatment discontinuation and treatment interruptions. And then because it's non-viral, the handling is very easy. It slides into the practice. And already now, you know, we believe that we will land up with probably years of storage in just a regular freezer and, you know, months, multiple months of storage in a fridge. So you put that all together, you know, detalimogene really fits the needs of the urologist. Yeah, let's expand upon that a little bit. Maybe talk a bit about a bit more about what proportion of patients with HR-NMIBC are managed in the community setting throughout their treatment journey, in a way. Yeah, what are some of the key considerations, how community physicians manage those patients as opposed to academic physicians? Yeah, so when you think about the segments, right, so what are the segments in this NMIBC space? You've got your academic physicians. You've got your community hospitals or community hospital systems, the LUGPAs, which are actually a collection of hospitals and individual practices. So think about those practices: two, three, four, five physicians, right? So those are the different segments. There were some data suggested about two-thirds where the patients were in the community setting. But our recent market research, and again, this is market research looking at claims data, suggests that over 80% of the physicians of the patients are in the community setting. So most of the patients are in the community. So and when you think about that, it makes a lot of sense, right? Like, how are you diagnosed with NMIBC? Usually it's men, mid-70s, where there's some blood in their urine, right? And so they go to their primary care doctor. They get referred to their local urologist. So that makes a lot of sense. So then, as I was saying before, those community urologists, very busy practices, very focused on throughput, really need an agent that fulfills the needs of both efficacy, great tolerability, and ease of use. And detalimogene, with a competitive efficacy profile, a best-in-class tolerability profile, and a unique non-viral approach, really fits the needs of those community urologists. Yeah. And so there's been a lot of innovation recently in the NMIBC space. Last year we saw J&J's INLEXZO approval, which became the latest, you know, new therapy in the space that to reach the market. As you look at this potential launch, sort of ahead of your own program, you know, reaching that stage, how will you look at this launch and how much read-through is there to the market, do you think? How will you be tracking that launch to inform the commercial opportunity for detalimogene? Yeah, Michael, well, first of all, you know, I, I was relatively new to the bladder cancer space and NMIBC. I was shocked at the standard of care. You know, effectively you have backordered BCG, and you have removal of bladder and a bunch of other things in between. So this is a new dawn for patients in NMIBC, having all these new agents. So it's very exciting for patients. I believe as well the approval of the J&J product, TAR-200, is really exciting as well. And it's important that that product does well, from my perspective. And why is that? Because first of all, for all of these products, none of these products have a 12-month CR rate of 80%-90%. They're all 20%-40-ish%, which means you have recurrence of about 60%-80%. Recurrence, but not progression. So progression would be very bad. Recurrence means you can use other medicines. So, having a successful TAR-200 launch is important because that just builds the prevalent population. So that's the first point. We're looking for something that's successful. The second thing that we are looking for is, you know, the folks at J&J set a new price point, right? And that new price point relative to the other agents is significantly different. So sitting back and watching their process through pricing and reimbursement and how it works through the channel will be very interesting for us. Because one of the nice advantages about detalimogene is, of the immunotherapies, we probably have the lowest cost of goods because we have four simple ingredients. So we have a lot of flexibility from a pricing perspective. If J&J is successful at that price point, that would really make a material difference in the valuation of our organization. So to me, really two things we're looking for is launch effectiveness. I think we feel pretty confident that this is going to be a big and important drug. It's actually the drug, with detalimogene that'll be used in the community. So we're keen to see good uptake there and second, you know, really tracking to see what happens from a pricing and reimbursement perspective. Yeah, I think a lot of us are watching that. And then maybe shifting over to talk about your own program. Obviously you are in the LEGEND study, which is your pivotal study. You did report some interim data last November on around 30 patients. Just remind us of the key takeaways from that interim update. Yeah, so I, I think for us so the first the first update is we're delighted that we fully enrolled the study, right? We targeted 100 patients. We actually couldn't stop there was so much interest it, you know, couldn't stop it. It landed up being 125 patients. So that's the first thing that we're delighted about. So we're, we're done, and it's a pivotal program. I think the second thing that we're, we're really pleased about is the profile is emerging, is a very competitive profile. We showed a, a six-month complete response rate of 62%, which is in line with, with the other agents. So that's very exciting to us. But I think on top of that, as I said before, what community urologists also value is tolerability. And I think it's overlooked, the, the quality of tolerability that we have. So we had 44% AEs at any time. Most of the other agents are, you know, 60%, 70%, 80%, 80%. Our AEs are mostly associated with the catheterization, so not very serious. But then one metric I think is really important is when you start looking at things like treatment interruptions and discontinuation. So these are indicators that people are having a hard time with the medicines. Ours are very low. You know, they're in, you know, they're in 1% or 2% range, whereas other agents are 40s%, 20s%, and the like, right? So the tolerability profile is looking like it's best in class. So we have a competitive and emerging competitive efficacy profile, emerging best-in-class tolerability profile. Put that together with the unique non-viral approach, I think it really does fit the needs of our urology community. Yeah. Do you have, can you provide any visibility or have you talked about response durability, perhaps beyond the six-month CR rate that you've reported? You know, how are those trending, relative to your expectations towards that 12-month time point? Well, we feel pretty confident, right? So, you know, first of all, if you think about durability, our preclinical models would suggest we'd have good durability. We have it's immunotherapy. And in general, you know, immunotherapies are durable. If you look at, you know, so from the data update that we did in November of last year, we only had five patients at the nine-month mark that could be evaluated, and five of five of those were in complete response, right? And if you look at all the other agents, you see sort of the decay curve from six months, nine months to 12 months. It's roughly the same. So if you put that all together, I think we feel pretty confident that, you know, we'll have a highly durable product. So on top of, you know, having a CR rate that's competitive, durable product, and a tolerable product, we think the profile look is looking very good. Yeah. And I think I may be wrong, but I think you adjusted the primary endpoint of the study as well to best ORR from the 12-month CR rate. Is that correct? And what drove that change? Yeah, so previously the primary ORR was a landmark analysis at 12 months. But if you actually then look at what the products are being approved upon, we just align with the FDA's done with previous agents. And so that is the primary endpoint is complete response rate at any time. And we demonstrated, you know, a pretty competitive CR rate in the 60s, which is, you know, so roughly two-thirds, right? And that's where the average is for most of the agents. So we're right in line with the other agents. Yeah. Then I think you did go to top-line data in the second half of this year on this study. Just remind us again of, you know, any more granularity on timing, and yeah, how you're tracking towards that final readout. Yeah, we're pretty excited about that. As I said, we have 125 patients that are enrolled. We provided an update in the fall of last year, with particularly patients that were from a post-protocol perspective. Later this year we'll have, you know, the majority of those 125 patients through the majority of, you know, those that have reached the 12-month time frame will be there. So that'll be the definitive data set. And, you know, we're tracking well to provide that update later this year. Yeah. What, what else do you need to do in terms of regulatory interactions to support a filing with the data later this year? Yeah, so from a regulatory perspective, you know, we've really enjoyed a very good dialogue with the FDA. I think the first thing is, you know, the fact that we have this special regulatory guidance, right, where they said, you know, a single study, open label, around 100 patients will be sufficient for a full approval, not a conditional approval, a full approval. And that's been holding strong. And you see that, you know, the TAR-200 was approved on that basis. Subsequent to that, you know, the FDA has granted us RMAT designation, right, which, you know, gives us more privileges and more dialogue. And then on top of that, we receive CDRP, which is really quite an honor. So CDRP is a pilot program. Only one of nine companies get that, you know, nine companies get that in a year. We were one of nine companies. That actually allows us to have a better dialogue on the manufacturing front. If you think about being able to file out of the five modules, you know, there are two summary modules. The main ones are preclinical. That's already done sitting on the shelf for us. As I said to you earlier, the manufacturing, we're almost finished the FDA validation batches. So that we should be writing that probably next quarter. That'll be on the shelf. And then we will write shells for the clinical data. And so we'll just drop that data in and we will file. So I think we've enjoyed a really good, you know, dialogue with the regulators. I think they've been really working with us. And, you know, we're on track, you know, for filing in the second half of this year. Right. How you did have this trial amendment last year, obviously to bring the study design in line with industry standard in a way. There were some patients treated as part of the study prior to the amendment. Will those be included or will the regulatory decision be on this new batch of patients post-amendment? Yeah, so we have 125 patients enrolled in the study, which is, you know, my understanding, the largest study, you know, this largest program in this space. Of that, 94 are post-amendment patients, you know, 94 patients. And the balance are pre-amendment, 31 patients. So at the end, the results are going to be largely driven by well, they'll be largely driven by the post-amendment patients. The 31 patients, which represents 20%-25%, we'll have a discussion with the FDA, you know, during the early part of this year around the statistical analysis plan. In earlier discussions, they've already spoken to us about some of those patients are just not going to be included. And so, as I said before, it's going to be driven by the post-amendment patients. The pre-amendment are almost de minimis at 31. They're going to be I don't know what the word is for more de minimis, right? They're going to not really drive the result very much. Makes sense. And then we, we just spoke earlier briefly, but obviously some companies are having difficulty with their CMC process, the manufacturing aspects of, of their product. So how does that, how does it look for detalimogene in terms of the CMC process and some of the regulatory requirements to support submission? Yeah, we're in very good shape. It's a huge competitive advantage for us having a unique non-viral approach. So we're different from many of the other agents. So we had already been manufacturing at scale for quite some time. You know, our product, it's a little bit different. Usually you do drug substance and drug product. You do three batches and three batches. We actually have three drug substances. That's the uniqueness. So we have 12 batches to get through for FDA validation. So that's fairly complicated, but we're almost done. We're almost done, so we're pretty much done there. And on top of that, we have the CDRP. CDRP allows us to go to the FDA. And rather than, you know, putting module three together and throwing it over the fence to them, we actually open up our files to them earlier. We have a very good dialogue back and forth. They give us feedback on various aspects. I think it really de-risks our filing. If I think about, you know, if I think about the risk, there's always risk in any filing, right? If you look historically, it used to be clinical would result in complete response letters. Increasingly, it's been manufacturing. I think in both cases, I think we feel pretty confident that we're going to be there with both of them. Right. Okay. And then, yeah, how do you think about the broader opportunity for detalimogene in other patient segments? Can you remind us what other cohorts you're evaluating in the LEGEND study and how that could, perhaps lead to other label expansions in the future? Yeah, in addition to the BCG, you know, unresponsive patients, we also have a BCG naive cohort. We have a BCG exposed cohort. And we have a papillary cohort. We're very focused, though, on cohort one, right? Because that's the cohort where you're getting an approval for. And so that's where we focus most of our energies. We've almost deprioritized the others, but we'll get back to those. They're important because they provide extra information for the medical community and potentially some NCCN guidelines. So, you know, we'll kind of reactivate those, and they'll provide some supplementary information as we get towards approval and potential launch. Okay. And then there's been some increasing interest recently in intermediate risk and NMIBC as well. Is that something that's on the radar for enGene? Absolutely. Absolutely. Because the profile fits really well for intermediate. Because if you think of, you know, high-risk BCG-resistant patients, those are tougher patients, intermediate is a lower disease burden. And what do you want for intermediate patients? You don't want, you don't want an elephant gun for that. That's hard to administer. You want something that is easy for the patient, easy for the physician. So we think that our product profile fits very nicely in, in, in intermediate risk. So it's something that, you know, we have in our sights to, to get to. But again, we want to be very focused. We want to make sure that we get the product across the line and then expand its uses into other areas over time. But the potential for detalimogene, particularly because of its relatively low cost of goods across multiple different types, bladder cancer, or other diseases, is pretty significant. Right. Then, with the, you know, top-line data approaching the second half, filing thereafter, what are your plans for commercialization of detalimogene in the U.S. and perhaps the rest of the world? And how much, you know, how do you think about a commercial buildout? So our go-to-market strategy, if you look at it from a regional perspective, in the U.S., our plan is to go alone. I'll go into that in a little bit greater detail. For Europe, we'll sort of evaluate. That's a financial decision. You know, I would say for most companies, they shouldn't go to Europe. I have quite a bit of experience in Europe, having been President of Europe for Bristol-Myers Squibb. Our head of commercialization has also had a lot of experience in Europe. We have the expertise to do it. That's pretty much a financial decision. Is it better for us to do it or for anybody else? The rest of the world, we would anticipate a partnership for. As it relates to the U.S., we've already geared up the machine, right? As I said, you know, we have a head of commercialization within the organization. We have on the ground already medical affairs individuals that are preparing the market. And we would anticipate we would need somewhere between 40-60 sales representatives, you know, in the U.S. So, you know, not a not an insurmountable infrastructure for a biotech of our size. So very, very manageable, you know, for us. And right now we're doing a lot of market research to sort of understand the customer base, where those where those key doctors are. And, you know, we're just starting the buildout. We're starting the buildout now. So we're going to be ready to launch. And we're looking forward to a good launch. I know it's early, but from a pricing strategy perspective, is TAR-200 a new benchmark for others in this space, or how do you think about pricing? It is a new benchmark. That's a huge lever for us and a big competitive advantage for us. If you look at the agents, the first agents were, you know, of orders of magnitude $250,000 a year. Then it was $500,000 in TAR, roughly $700,000. That's moved the benchmark up. If you look in the immunotherapies, you know, because we have this low-cost manufacturing, our cost of goods are competitively lower than other agents. We can make it at scale. What does that allow us to do? It allows us to look at the marketplace and just to see how things play out. You know, I've priced lots of products in my life, right? You don't do it till the very last minute. We'll be able to thread the needle absolutely perfectly. Because the issue with pricing, particularly in a buy-and-bill model, is we want to price where it's attractive for the practices, where they can generate good revenue. But you don't want to price that's not commensurate with the value that you're bringing. And we actually think with detalimogene that we have the flexibility to move up and down as the market changes. And that's a huge advantage for us. Right. Great. Well, I think that's all I had. So looking forward to the top-line data in the second half and then, the pre-commercial prep, kicking off or continuing this year. So thank you so much, Ron. Really appreciate all the updates. Yeah, thanks, and t hanks for the opportunity. Good to be here. Thanks.